Immune negative checkpoint regulator (NCR) pathways have proven to be extraordinary clinical targets in the treatment of human immune-related diseases. Blockade of two NCRs, CTLA-4 and PD-1, using monoclonal antibodies (mAbs) to enhance tumor immunity is revolutionizing the treatment of cancer and has established these pathways as clinically validated targets in human disease. More recently, soluble versions of NCR ligands that trigger NCR pathways have entered the clinic as immunosuppressive drugs to treat autoimmunity (i.e., AMP-110/B7-H4-Ig for Rheumatoid arthritis), and early clinical results are eagerly awaited.
VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation (1), is a recently-identified, NCR ligand, whose closest phylogenetic relative is PD-L1. Like PD-L1, VISTA is a ligand that profoundly suppresses immunity (1), and like PD-L1, blocking VISTA allows for the development of therapeutic immunity to cancer in pre-clinical oncology models (2). Whereas blocking VISTA enhances immunity, especially CD8+ and CD4+ mediated T cell immunity, treatment with a soluble Ig fusion protein of the extracellular domain of VISTA (VISTA-Ig) suppresses immunity and has been shown to arrest the progression of multiple murine models of autoimmune disease.
Clear scientific evidence has shown that VISTA is a ligand that induces profound T cell suppression; however, the identity of the receptor that transduces this suppressive effect is currently unknown. Identification of receptors in the field of NCR pathways has been particularly challenging given their extremely low uM affinity and low density.
Herein we present experimental methods which have identified that “V-Set and Immunoglobulin domain containing 8” as the receptor for VISTA (hereinafter “V-R” or “VSIG8”). We further disclose assays that validate that VSIG8 specifically interacts with VISTA in vitro and in vivo and that the interaction of VISTA with VSIG8 has a suppressive effect on T cell activation, proliferation and/or immune cytokine production.
The identification of VSIG8 as the receptor for VISTA has much clinical and scientific promise. It is known that VISTA antagonists, e.g., αVISTA mAbs are useful as therapeutics in the treatment of oncology and infection. Also, fragments of VISTA may be used as VISTA antagonists and are potentially useful as therapeutics in the treatment of oncology and infection. Further, VISTA polypeptides, e.g., VISTA-Ig fusion proteins have been demonstrated to be useful in preventing and treating autoimmunity, inflammation and allergic disorders.
Therefore, VSIG8 will similarly be useful as it will provide a second, independent target for the development of VISTA-R agonists and antagonists. Indeed, with regard to receptors in the B7 family, the most effective therapeutics to emerge thus far are (αCTLA4 {Yervoy} and αPD-1 {Novolumab}) which both are antibodies that block receptor signaling rather than antibodies to the respective ligands.
Therefore, antibodies to VSIG8 which block or inhibit the VISTA/VISTA-R interaction should be effective in treating oncology and infectious disease. Particularly, VISTA-R antagonists will be potentially useful in the treatment of cancer or infectious disease indications such as melanoma and lung cancer or HIV infection. By contrast, VISTA-R agonists which promote or enhance the VISTA/VISTA-R binding interaction will potentially be useful in the treatment of autoimmune, allergic, and inflammatory indications, GVHD, transplant or other indications wherein the suppression of T cell activation, T cell proliferation or cytokine production is desired.
Moreover, the identification of the V-R will greatly expedite the clinical development of VISTA-Ig as an immunosuppressive drug, and further facilitate the ascertainment of pharmacodynamics, target engagement, and pharmacokinetic studies, which may be used to ascertain the level of receptor occupancy required to produce optimal clinical results.
The present invention satisfies these objectives by identifying VSIG8 as the receptor for VISTA.